17alpha, 21-substituted methylenedioxy pregnadienes



United States Patent 3,139,427 17a,21-SUBSTITUTED METHYLENEDIOXY PREGNADIENES Milton Heller and Seymour Bernstein, New City, N.Y., assignors to American Cyanamid Company, Stamford,

Conn a corporation of Maine N0 Drawing. Filed Dec. 19, 1962, Ser. No. 245,684 4 Claims. (Cl. 260239.55)

This invention relates to new steroid compounds. More particularly, it relates to Hall-substituted methylenedioxy steroids of the pregnane series.

The novel steroids of the present invention can be i1- lustrated by the following structural formula:

wherein R is selected from the group consisting of hydrogen and lower alkanoyl, R and R is selected from the group consisting of hydrogen and lower alkyl, one of which is lower alkyl and X is selected from the group consisting of 0:0 and IG radicals.

The compounds of the present invention are, in general, crystalline solids and are insoluble in water. They are crystallizable from organic solvents such as toluene, benzene, petroleum ether and the like or mixtures of organic solvents such as benzene-toluene, acetone-petroletun ether or acetone-benzene.

The present compounds are prepared by reacting a l7a,21-dihydroxy steroid of the pregnane series with a dialkoxyalkane in the presence of dimethylformarnide and p-toluenesulfonic acid. The reaction can be carried out at a temperature within the range of about 60 to 150 C. It is usually convenient and desirable to carry out the reaction at the refluxing temperature of the solvent used. The reaction is complete in a period of from about hours to several days depending on temperature used.

In carrying out the present process the dialkoxyalkanes (having alkoxy groups on same carbon atom) can be, for example, dirnethoxypropane, diethoxypropane, dimethoxybutane, diethoxybutane, dimethoxypentane, diethoxypentane, dimethoxyhexane, diethoxyhexane and the like.

The present compounds are physiologically active as anti-inflammatory agents and are useful as components of preparations for treating dermatological and opthalmic disorders.

The following examples show in detail the preparation of representative Hull-substituted methylenedioxy steroids of the pregnane series.

3,139,427 Patented June 30, 1964 ice EXAMPLE I Preparation of 16u-Acet0xy-9a-Fluor0-11p-Hydroxy-1 c, 21-Is0pr0pylidenedioxypregna-l4-Diene-3,20-Dione A solution of 16a-acetoxy-9a-fluoro-11B,17a,21-trihydroxypregna 1,4 diene 3,20 dione (2.29 g.) [1. Am. Chem. Soc., 82, 4625 (1960)] and p-toluenesulfonic acid monohydrate (55 mg.) in 2,2-dimethoxypropane (34 m1.) and dimethylformamide (11.5 ml.) is refluxed for 96 hours. The reaction mixture still gives a positive but weak Blue Tetrazolium test. Solid sodium bicarbonate is added to the solution and most of the liquid is removed in a stream of air at C. Water and ethyl acetate are added to the residue and after separation the water layer is further extracted with ethyl acetate. The combined ethyl acetate solutions are dried and the solvent removed under reduced pressure. The resultant uncrystallizable oil (2.86 g.) is submitted to chromatography on a magnesium silicate column (200 g.). Elution with acetone-petroleum ether (60-70 C.) (6:19) gives a solid 16a-acetoxy-9a-fluoro-11B-hydroxy-l7a,2lisopropylidenedioxypregna-1,4 diene 3,20 dione which upon crystallization from acetone-petroleum ether gives melting point 285.5286 C.

EXAMPLE II Preparation of 9a-Flu0ro-1118,16a-Dihydroxy-17a,21-Is0- Propylidenedioxypregna-I ,4-Diene-3,20-Dione A solution of 0.5 g. of 16a-acetoxy-9u-fluoro-llfi-hydroxy-l7ot,21-isopropylidenedioxypregua-1,4-diene 3,20- dione in 50 ml. of methanol and 10 ml. of 10% potassium carbonate solution is allowed to stand 20 minutes under nitrogen. The solution is then neutralized with acetic acid and is concentrated at room temperature. The addition of water gives 9a-fluoro-1lfi,l6a-dihydroxy-17oc, 2l-isopropylidenedioxypregna-1,4-diene 3,20 dione as a precipitate which is collected.

EXAMPLE III Preparation of 16u-Acet0xy-9u-Flu0r0-1 7a,21-Isopr0pylidenedioxypregna-I ,4-Diene-3,1 1,20-Tri0ne A solution of 0.5 g. of 16a-acetoxy-9ot-fluoro-1Iii-hydroxy-17a,2l-isopropylidenedioxypregna-1,4-diene 3,20- dione in 5 ml. of pyridine is added to a slurry 0.5 g. of chromium trioxide in 5 ml. of pyridine. After standing at room temperature 16 hours, the mixture is poured into water and is filtered. The filtrate is extracted with ethyl acetate and the solution is dried. Removal of the solvent under reduced pressure gives a solid which is acetoxy-9a-fluoro-17a,21-isopropylidenedioxypregna 1,4- diene-3,11,20-tri0ne.

We claim:

1. A compound of the formula:

r, a 4 wherein R is selected from the group consisting of hy- 3. The compound 16a-acetoxy-9ot-fiuoro- 1711,21 -isodrogen and lower alkanoyl, R and R" are lower alkyl propylidenedioxypregna-1,4-diene-3,11,20-trione. and X is selected from the group consisting of 4. The compound 9ot-fluoro-11p,16a-dihydroxy-17a,21-

O (6) isopropylidenedioxypregna-1,4-diene-3,20-dione. and 5 References Cited in the file of this patent I m UNITED STATES PATENTS a 3,081,299 Robinson et a1. Mar. 21, 1963 radicals.

2. The compound 16a-acetoxy-9a-fluoro-1lp-hydroxy- 10 OTHER REFERENCES 17a,21-isopropylidenedioxypregna-1,4-diene-3,20-dione. Tanabe et al.: J.A.C.S., 83, pp. 756-57 (1961). 

1. A COMPOUND OF THE FORMULA: 